This proposal is to support the training of Dr. Daniel Fitzgerald in international biomedical research. The applicant will be mentored by Warren Johnson and John Ho (Cornell University Medical College ) and David Ho (Aaron Diamond AIDS Research Center) in New York and Jean Pape (GHESKIO) in Haiti. The initial research training will be undertaken at the NIH-funded Cornell-GHESKIO unit in Port-au-Prince, Haiti with a third year primarily in New York. The proposed research is based on two hypotheses: 1) the incidence of HIV heterosexual transmission among discordant couples is greatest in the early post-infection period of the index partner; 2) highly exposed, persistently HIV-seronegative spouses are protected from infection by innate or acquired host factors. The specific aims of this proposal are: 1) constitute and characterize a cohort of HIV discordant couples in which the index partner was recently infected; 2) determinate the incidence of HIV infection in the HIV-seronegative spouses; and 3) characterize innate and acquired host resistance factors in the exposed but uninfected partner, including CCR5 promoter mutations and genital mucosal IgA and other potential anti-HIV factors. Preliminary studies of highly HIV-exposed persistently HIV- seronegative spouses of HIV-infected persons have identified a CCR5 promoter mutation that reduces in vitro transcription of CCR5, thereby potentially protecting against HIV infection. This mutation appears to be unique to persons of African descent. The identification of the period of greatest risk for HIV heterosexual transmission in HIV-discordant couples will permit the targeting of limited intervention resources to these persons (condoms, counseling, STD screening, antiretrovirals). This data and a better understanding of innate and acquired host resistance will also be essential for the optimal design of HIV vaccine efficacy trials.